Selective C-H Iodination of Weinreb Amides and Benzamides through Iridium Catalysis in Solution and under Mechanochemical Conditions.

The acid mediated ortho-iodination of Weinreb amides using a readily available catalyst is described. The selective ortho-iodination of Weinreb amides, challenging substrates in directed C-H activations, and also of benzamides is achieved. The process works under mild conditions and tolerates air and moisture, having a great potential for industrial applications. The methodology can be applied under mechanochemical conditions maintaining the reaction outcome and selectivity.

Synthesis of α,α-Diaryl-α-amino Acid Precursors by Reaction of Isocyanoacetate Esters with o-Quinone Diimides.

A novel procedure for the synthesis of α,α-diaryl-α-amino acid derivatives has been developed. Silver oxide catalyzes the conjugate addition of α-aryl isocyanoacetates to o-quinone diimide, affording the corresponding α,α-diarylisocyano esters in excellent yields and regioselectivities in short reaction times. Acid hydrolysis of the isocyano group provides the corresponding amino acids bearing a diarylated tetrasubstituted carbon atom. The reaction is also amenable to the synthesis of α-alkyl-α-arylisocyano esters, while the reaction with 3-hydroxy o-quinone diimides provides 4H-benzo[e][1,3]oxazines via a conjugate addition/cyclization process.

A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides.

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

Organocatalytic enantioselective Mannich reaction of isoxazol-5(4H)-ones to isatin-derived ketimines.

An efficient organocatalytic asymmetric Mannich reaction between isoxazol-5(4H)-ones and isatin-derived ketimines has been developed. A bifunctional squaramide/Brønsted base organocatalyst catalyzed the enantioselective Mannich addition to afford chiral 3-aminooxindoles bearing a tetrasubstituted stereocenter at C3 decorated with an isoxazole moiety in good yields and with excellent enantioselectivities. Additionally, several synthetic transformations were described showing the versatility of the prepared compounds.

An Expedient Method for the Umpolung Coupling of Enols with Heteronucleophiles.

In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatom nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2 . The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1λ3 [d][1,2]iodaoxole, which provides a key α-brominated carbonyl intermediate. The reaction mechanism has been studied experimentally and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen-bonded bromide.

Metal-Free Diastereo- and Enantioselective Dearomative Formal [3 + 2] Cycloaddition of 2-Nitrobenzofurans and Isocyanoacetate Esters.

The diastereo- and enantioselective dearomative formal [3 + 2] cycloaddition of 2-nitrobenzofurans and α-aryl-α-isocyanoacetate esters provides tricyclic compounds bearing the 3a,8b-dihydro-1H-benzofuro[2,3-c]pyrrole framework with three consecutive stereogenic centers. The reaction was enabled by a cupreine-ether organocatalyst. The reaction products were obtained with almost full diastereoselectivity and with excellent enantiomeric excesses for a number of substituted 2-nitrobenzofurans and isocyanoacetates.

Unraveling the Mechanism of the IrIII -Catalyzed Regiospecific Synthesis of α-Chlorocarbonyl Compounds from Allylic Alcohols.

We have used experimental studies and DFT calculations to investigate the IrIII -catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization-chlorination of allylic alcohols into α-chlorinated carbonyl compounds. The mechanism involves a hydride elimination followed by a migratory insertion step that may take place at Cß but also at Cα with a small energy-barrier difference of 1.8 kcal mol-1 . After a protonation step, calculations show that the final tautomerization can take place both at the Ir center and outside the catalytic cycle. For the isomerization-chlorination reaction, calculations show that the chlorination step takes place outside the cycle with an energy barrier much lower than that for the tautomerization to yield the saturated ketone. All the energies in the proposed mechanism are plausible, and the cycle accounts for the experimental observations.

Enantioselective zinc-mediated conjugate alkynylation of saccharin-derived 1-aza-butadienes.

The enantioselective 1,4-alkynylation of conjugated imines derived from saccharin with aryl- and alkyl-substituted terminal alkynes has been achieved. The reaction mediated by diethylzinc in the presence of a catalytic amount of a bis(hydroxy)malonamide chiral ligand provides the corresponding imines bearing a propargylic stereocenter with moderate yields and fair to excellent enantioselectivities.

Three-Component Synthesis of α-Aminoperoxides Using Primary and Secondary Dialkylzinc Reagents with O2 and α-Amido Sulfones.

A straightforward strategy for the synthesis of unprecedented α-aminoperoxides bearing primary and secondary alkylperoxide substituents is described. Commercially available dialkylzinc reagents are oxidized with molecular oxygen and the consequent peroxide species react with stable (hetero)aromatic and aliphatic α-amido sulfones in excellent yields (>90%). The now available α-aminoperoxides are of potential interest in medicinal chemistry, specifically for the synthesis of antimalarial compounds. Moreover, modification of the reaction conditions selectively leads to N,O-acetals in good yields.

Stereospecific Isomerization of Allylic Halides via Ion Pairs with Induced Noncovalent Chirality.

A regioselective protocol for the synthesis of substituted allylic chlorides, bromides, and fluorides has been established. Remarkably, the method can be applied to the enantioselective synthesis of challenging chiral allylic chlorides. When the allylic halides are treated with the base triazabicyclodecene as the catalyst, a [1,3]-proton shift takes place, giving the corresponding vinyl halides in excellent yields with excellent Z:E ratios. Furthermore, the [1,3]-proton shift takes place with an outstanding level of chirality transfer from chiral allylic alcohols (≤98%) to give chiral trifluoromethylated vinyl chlorides.

An umpolung strategy to react catalytic enols with nucleophiles.

The selective synthesis of α-functionalized ketones with two similar enolizable positions can be accomplished using allylic alcohols and iridium(III) catalysts. A formal 1,3-hydrogen shift on allylic alcohols generates catalytic iridium-enolates in a stereospecific manner, which are able to react with electrophiles to yield α-functionalized ketones as single constitutional isomers. However, the employment of nucleophiles to react with the nucleophilic catalytic enolates in this chemistry is still unknown. Herein, we report an umpolung strategy for the selective synthesis of α-alkoxy carbonyl compounds by the reaction of iridium enolates and alcohols promoted by an iodine(III) reagent. Moreover, the protocol also works in an intramolecular fashion to synthesize 3(2H)-furanones from γ-keto allylic alcohols. Experimental and computational investigations have been carried out, and mechanisms are proposed for both the inter- and intramolecular reactions, explaining the key role of the iodine(III) reagent in this umpolung approach.

Catalytic Diastereo- and Enantioselective Synthesis of 2-Imidazolinones.

Chiral cyclic ureas (2-imidazolinones) were prepared by the reaction of nitrones and isocyanoacetate esters using a multicatalytic system that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag+ as a Lewis acid. The reaction could be achieved with a range of nitrones derived from aryl- and cycloalkylaldehydes with moderate diastereo- and good enantioselectivity. A plausible mechanism involving an initial formal [3 + 3] cycloaddition of the nitrone and isocyanoacetate ester, followed by rearrangement to an aminoisocyanate and cyclization to the imidazolinone, is proposed.

Enantioselective Synthesis of 5-Trifluoromethyl-2-oxazolines under Dual Silver/Organocatalysis.

The first enantioselective formal [3 + 2] cycloaddition between α-isocyanoesters and trifluoromethylketones to give 5-trifluoromethyl-2-oxazolines bearing two contiguous stereogenic centers, one of them being a quaternary stereocenter substituted with a CF3 group, has been developed. The reaction is based upon a multicatalytic approach that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag+ as Lewis acid. The reaction could be achieved with a range of aryl and heteroaryl trifluoromethyl ketones, and the resulting oxazolines were obtained with good to excellent diastereo- and enantioselectivity.

Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates.

The first method to access unsymmetrical aliphatic acyloins is presented. The method relies on a fast 1,3-hydride shift mediated by an IrIII complex in allylic alcohols followed by oxidation with TEMPO+ . The direct conversion of allylic alcohols into acyloins is achieved in a one-pot procedure. Further functionalization of the Cα' of the α-amino-oxylated ketone products gives access to highly functionalized unsymmetrical aliphatic ketones, which further highlights the utility of this transformation.

Enantioselective synthesis of chiral oxazolines from unactivated ketones and isocyanoacetate esters by synergistic silver/organocatalysis.

A multicatalytic approach that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag+ as Lewis acid has been applied in the reaction of unactivated ketones with tert-butyl isocyanoacetate to give chiral oxazolines bearing a quaternary stereocenter. The formal [3+2] cycloaddition provided high yields of the corresponding cis-oxazolines with good diastereoselectivity and excellent enantioselectivity, being applied to aryl-alkyl and alkyl-alkyl ketones.

Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing.

A mild base-catalyzed strategy for the isomerization of allylic alcohols and allylic ethers has been developed. Experimental and computational investigations indicate that transition metal catalysts are not required when basic additives are present. As in the case of using transition metals under basic conditions, the isomerization catalyzed solely by base also follows a stereospecific pathway. The reaction is initiated by a rate-limiting deprotonation. Formation of an intimate ion pair between an allylic anion and the conjugate acid of the base results in efficient transfer of chirality. Through this mechanism, stereochemical information contained in the allylic alcohols is transferred to the ketone products. The stereospecific isomerization is also applicable for the first time to allylic ethers, yielding synthetically valuable enantioenriched (up to 97% ee) enol ethers.

Catalytic Enantioselective Conjugate Alkynylation of ß-Aryl-ß-trifluoromethyl Enones Constructing Propargylic All-Carbon Quaternary Stereogenic Centers.

The enantioselective conjugate alkynylation of ß-aryl-ß-trifluoromethyl enones has been carried out using terminal alkynes and diethylzinc in the presence of 3,3'-bis(perfluorophenyl)BINOL as the chiral ligand to give the corresponding ketones bearing a trifluoromethylated propargylic quaternary stereocenter with fair to good enantioselectivities. Enones bearing a bulky 2-naphthyl attached to the carbonyl group provided the best enantioselectivities. The synthetic applicability of the resulting products has been demonstrated with their iodocyclization to form 4H-pyrans.

Catalytic Enantioselective Conjugate Alkynylation of α,ß-Unsaturated 1,1,1-Trifluoromethyl Ketones with Terminal Alkynes.

The first catalytic enantioselective conjugate alkynylation of α,ß-unsaturated 1,1,1-trifluoromethyl ketones has been carried out. Terminal alkynes and 1,3-diynes were treated with trifluoromethyl ketones in the presence of a low catalytic load of a Cu(I) -MeOBIPHEP complex (2.5 mol %) and triethylamine (10 mol %) to give the corresponding trifluoromethyl ketones bearing a propargylic stereogenic center at the ß position with good yields and excellent enantiomeric excesses in most of the cases. No 1,2-addition products were formed under the reaction conditions. The procedure showed broad substrate scope for alkyne, diyne, and enone. A rationale for the observed stereochemistry has been provided. Finally, the potential application of the reaction products in the synthesis of chiral tetrahydrofurans bearing a trifluoromethylated quaternary stereocenter has been devised.

Highly enantioselective copper(I)-catalyzed conjugate addition of 1,3-diynes to α,ß-unsaturated trifluoromethyl ketones.

The conjugate diynylation of α,ß-unsaturated trifluoromethyl ketones is carried out in the presence of a low catalytic load (2.5 mol%) of a copper(I)-MeOBIPHEP complex, triethylamine and a terminal 1,3-diyne. Pre-metalation of the terminal 1,3-diyne with stoichiometric or higher amounts of dialkylzinc reagent is not required. The corresponding internal diynes bearing a propargylic stereogenic center are obtained with good yields and excellent enantioselectivities.

Hydroxyl-directed stereoselective diboration of alkenes.

An alkoxide-catalyzed directed diboration of alkenyl alcohols is described. This reaction occurs in a stereoselective fashion and is demonstrated with cyclic and acyclic homoallylic and bishomoallylic alcohol substrates. After oxidation, the reaction generates 1,2-diols such that the process represents a method for the stereoselective directed dihydroxylation of alkenes.